An Evaluation of μ-Opioid Receptor (OPRM1) as a Predictor of Naltrexone Response in the Treatment of Alcohol Dependence: Results From the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) Study

Center for Drug and Alcohol Programs, Medical University of South Carolina, 67 President St, PO Box 250861, Charleston, SC 29425, USA.
Archives of general psychiatry (Impact Factor: 14.48). 03/2008; 65(2):135-44. DOI: 10.1001/archpsyc.65.2.135
Source: PubMed


Naltrexone hydrochloride treatment for alcohol dependence works for some individuals but not for everyone. Asn40Asp, a functional polymorphism of the mu-opioid receptor gene (OPRM1), might predict naltrexone response.
To evaluate whether individuals with alcoholism who are heterozygous (Asp40/Asn40) or homozygous (Asp40/Asp40) for the OPRM1 Asp40 allele respond better to naltrexone.
Pharmacogenetic analysis conducted between January 1, 2001, and January 31, 2004.
Eleven academic sites in the COMBINE Study.
Recently abstinent volunteers who met all 3 of the following conditions: (1) DSM-IV criteria for primary alcohol dependence; (2) participation in the COMBINE Study; and (3) availability of DNA.
Alcoholic subjects were treated for 16 weeks with 100 mg of naltrexone hydrochloride (234 Asn40 homozygotes and 67 with at least 1 copy of the Asp40 allele) or placebo (235 Asn40 homozygotes and 68 with at least 1 copy of the Asp40 allele). All participants received medical management (MM) alone or with combined behavioral intervention (CBI).
Time trends in percentage of days abstinent, percentage of heavy drinking days, and rates of good clinical outcome.
Alcoholic subjects with an Asp40 allele receiving MM alone (no CBI) had an increased percentage of days abstinent (P = .07) and a decreased percentage of heavy drinking days (P = .04) if treated with naltrexone vs placebo, while those with the Asn40/Asn40 genotype showed no medication differences. If treated with MM alone and naltrexone, 87.1% of Asp40 carriers had a good clinical outcome, compared with only 54.8% of individuals with the Asn40/Asn40 genotype (odds ratio, 5.75; confidence interval, 1.88-17.54), while, if treated with placebo, 48.6% of Asp40 carriers and 54.0% of individuals with the Asn40/Asn40 genotype had a good clinical outcome (interaction between medication and genotype, P = .005). No gene x medication interactions were observed in those treated with both MM and CBI.
These results confirm and extend the observation that the functionally significant OPRM1 Asp40 allele predicts naltrexone treatment response in alcoholic individuals. This relationship might be obscured, however, by other efficacious treatments. OPRM1 genotyping in alcoholic individuals might be useful to assist in selecting treatment options. Identifier: NCT00006206.

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    • "Furthermore, individuals treated with naltrexone who had the Asp40 allele reported longer times to first relapse than their As- n40Asn counterparts. In a follow-up analysis of the COMBINE study, it was also shown that individuals with the Asp40 allele who received naltrexone had a lower percentage of heavy drinking days and a higher percentage of days abstinent from alcohol than naltrexone-treated individuals with the Asn40Asn variant or either placebo group (Anton et al., 2008). Recently,Kranzler et al. (2013a)demonstrated that Asp40-allele carriers treated with naltrexone were more likely to reduce nighttime drinking after having reported a greater desire to drink in the evening than Asn40Asn individuals. "
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    ABSTRACT: Alcohol use disorders (AUDs) represent a significant health burden worldwide. Currently, there are three medications approved by the U.S. Food and Drug Administration for the treatment of AUDs, and other drugs are being prescribed off-label for this purpose. However, response rates for pharmacologic treatment are low, and extant research suggests that treatment effects may partially depend on genetic factors. Personalized medicine, or using a patient's genetics and/or personal history to determine efficacy of treatment prior to prescription, is an emerging tool that will help clinicians treat their patients more effectively and safely. This review systematically discusses current findings from AUD pharmacotherapy trials examining disulfiram, acamprosate, naltrexone, the injectable naltrexone, and topiramate. Furthermore, it presents pharmacogenetics findings associated with these medications in an attempt to further the field of personalized medicine. Research from trials examining AUDs and comorbid major depressive disorder and anxiety disorders is also presented, and pharmacogenetic findings for these treatments are discussed. Lastly, the authors comment on the present and future states of the field of personalized medicine for AUD.
    No preview · Article · Oct 2015
    • "To date, however, only individual moderators of treatment effects have been considered in COMBINE (e.g. [2]) and " unsupervised " learning methods have been applied [3]. As an alternative to this approach, a systematic search of the large number of collected data on baseline predictors in order to identify subgroups with differential treatment effects would be valuable. "
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    ABSTRACT: The tree-based methodology has been widely applied to identify predictors of health outcomes in medical studies. However, the classical tree-based approaches do not pay particular attention to treatment assignment and thus do not consider prediction in the context of treatment received. In recent years, attention has been shifting from average treatment effects to identifying moderators of treatment response, and tree-based approaches to identify subgroups of subjects with enhanced treatment responses are emerging. In this study, we extend and present modifications to one of these approaches (Zhang et al., 2010 [29]) to efficiently identify subgroups of subjects who respond more favorably to one treatment than another based on their baseline characteristics. We extend the algorithm by incorporating an automatic pruning step and propose a measure for assessment of the predictive performance of the constructed tree. We evaluate the proposed method through a simulation study and illustrate the approach using a data set from a clinical trial of treatments for alcohol dependence. This simple and efficient statistical tool can be used for developing algorithms for clinical decision making and personalized treatment for patients based on their characteristics.
    No preview · Article · Jun 2015 · Statistics and its interface
    • "Previous investigations of naltrexone moderators have focused primarily on characteristics linked to biological vulnerability (Anton et al., 2008; Capone et al., 2011; Oroszi et al., 2009), including the l-opioid receptor gene (OPRM1), with the Asp40 allele associated with greater naltrexoneinduced blunting of alcohol reward (Ray and Hutchison, 2007; Setiawan et al., 2011) and stronger clinical response to naltrexone (Anton et al., 2008; Oslin et al., 2003). Fewer studies have examined psychosocial moderators of naltrexone effects. "
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    ABSTRACT: Background Oral naltrexone is an efficacious medication for treatment of alcohol dependence, but small effect sizes and variability in outcomes suggest the presence of person-level moderators of naltrexone response. Identification of contextual or psychosocial moderators may assist in guiding clinical recommendations. Given the established importance of social networks in drinking outcomes, as well as the potential effects of naltrexone in reducing cue reactivity which may be especially important among those with more heavy drinkers and more alcohol cues in their networks, we examined pretreatment social network variables as potential moderators of naltrexone treatment effects in the COMBINE study.Methods The sample included all COMBINE study participants in medication conditions with full data on the Important People Inventory (IPI) and covariates at intake (N = 1,197). The intake IPI assessed whether participants had any frequent drinkers in their network and the average frequency of contact with these drinkers. The effects of treatment condition, pretreatment network variables, and their interactions on percent heavy drinking days were tested in hierarchical linear models, controlling for demographics and baseline clinical covariates.ResultsIn treatment conditions involving medical management and combined behavioral intervention (CBI), the effects of active naltrexone on heavy drinking were significantly greater for individuals with frequent drinkers in their network (z = −2.66, p < 0.01) and greater frequency of contact with those drinkers (z = −3.19, p < 0.01). These network variables did not moderate the effects of active naltrexone without CBI.Conclusions When delivered in conjunction with behavioral interventions, naltrexone can be more potent for alcohol-dependent adults who have greater contact with frequent drinkers prior to treatment, which may indicate patterns of environmental exposure to alcohol. Contextual, social risk factors are a potential avenue to guide personalized treatment of alcohol dependence.
    No preview · Article · Jan 2015 · Alcoholism Clinical and Experimental Research
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